approval package for76-745 for oxybutynin chloride extended-release tablets, 15 mg, approved on...

CENTER FOR DRUG EVALUATION AND RESEARCH

Approval Package for:

APPLICATION NUMBER: ANDA 078293Orig1s000

Name: Oxybutynin Chloride Extended-release Tablets,15 mg

Sponsor: Mylan Pharmaceuticals, Inc.

Approval Date: May 10, 2007



CONTENTS

Reviews / Information Included in this Review Approval Letter X Tentative Approval Letter X Labeling X Labeling Review(s) X Medical Review(s) Chemistry Review(s) X Bioequivalence Review(s) X Statistical Review(s) Microbiology Review(s) Other Review(s) Administrative & Correspondence Documents X



APPROVAL LETTER

DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration Rockville, MD 20857

ANDA 78-293 Mylan Pharmaceuticals Inc. Attention: S. Wayne Talton Vice President, Regulatory Affairs 781 Chestnut Ridge Road P.O. Box 4310 Morgantown, WV 26504-4310 Dear Sir: This is in reference to your abbreviated new drug application (ANDA) dated May 2, 2006, submitted pursuant to section 505(j) of the Federal Food, Drug, and Cosmetic Act (the Act), for Oxybutynin Chloride Extended-release Tablets, 15 mg. Reference is also made to the tentative approval letter issued by this office on February 5, 2007, and to your amendments dated March 5, and April 17, 2007. We have completed the review of this ANDA and have concluded that the drug is safe and effective for use as recommended in the submitted labeling. Accordingly the ANDA is approved. The Division of Bioequivalence has determined your Oxybutynin Chloride Extended-release Tablets, 15 mg, to be bioequivalent and, therefore, therapeutically equivalent to the reference listed drug (RLD), Ditropan XL Extended-release Tablets of Alza Corporation (Alza). Your dissolution testing should be incorporated into the stability and quality control program using the same method proposed in your ANDA. The RLD upon which you have based your ANDA, Alza’s Ditropan XL Extended-release Tablets, 15 mg, is subject to periods of patent protection. The following patents and expiration dates (with pediatric exclusivity added) are currently listed in the agency’s publication titled Approved Drug Products with Therapeutic Equivalence Evaluations (the “Orange Book”): U.S. Patent Number Expiration Date 5,674,895 (the '895 patent) November 22, 2015

5,840,754 (the '754 patent) November 22, 2015 5,912,268 (the '268 patent) November 22, 2015 6,124,355 (the '355 patent) November 22, 2015 6,262,115 (the '115 patent) November 22, 2015 6,919,092 (the '092 patent) November 22, 2015 Your ANDA contains paragraph IV certifications to each of the patents under section 505(j)(2)(A)(vii)(IV) of the Act stating that the patents are invalid, unenforceable, or will not be infringed by your manufacture, use, or sale of Oxybutynin Chloride Extended-release Tablets, 15 mg, under this ANDA. Section 505(j)(5)(B)(iii) of the Act provides that approval of an ANDA shall be made effective immediately, unless an action is brought against Mylan Pharmaceuticals Inc. (Mylan) for infringement of one or more of the patents that were the subjects of the paragraph IV certifications. This action must have been brought against Mylan prior to the expiration of 45 days from the date the notice you provided under section 505 (j)(2)(B)(i) was received by the NDA/patent holder(s). You have notified the agency that Mylan complied with the requirements of section 505(j)(2)(B) of the Act, and within the statutory 45-day period litigation for infringement of the ‘355 patent was brought against Mylan in the United States District Court for the Northern District of West Virginia (Alza Corporation v. Mylan Laboratories Inc. and Mylan Pharmaceuticals Inc., Civil Action No. 1:06-cv-125). Mylan was not sued within the 45-day period on any of the other listed patents. You informed the agency that the case regarding the ‘355 patent was dismissed. Moreover, the 180-day exclusivity period of another applicant, discussed in our tentative approval letter of February 5, 2007, has expired. Therefore, under section 505(j)(5)(B)(iii)(I), your ANDA is eligible for approval. Under section 506A of the Act, certain changes in the conditions described in this ANDA require an approved supplemental application before the change may be made. Postmarketing reporting requirements for this ANDA are set forth in 21 CFR 314.80-81 and 314.98. The Office of Generic Drugs should be advised of any change in the marketing status of this drug. Promotional materials may be submitted to FDA for comment prior to publication or dissemination. Please note that these submissions are voluntary. If you desire comments on proposed launch promotional materials with respect to compliance with applicable regulatory requirements, we recommend you submit, in

draft or mock-up form, two copies of both the promotional materials and package insert(s) directly to:

Food and Drug Administration Center for Drug Evaluation and Research Division of Drug Marketing, Advertising, and Communications 5901-B Ammendale Road Beltsville, MD 20705

We call your attention to 21 CFR 314.81(b)(3) which requires that all promotional materials be submitted to the Division of Drug Marketing, Advertising, and Communications with a completed Form FDA 2253 at the time of their initial use.

Sincerely yours, {See appended electronic signature page} Gary Buehler Director Office of Generic Drugs Center for Drug Evaluation and Research

---------------------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.--------------------------------------------------------------------------------------------------------------------- /s/---------------------Gary Buehler5/10/2007 02:47:39 PM



TENTATIVE APPROVAL LETTER

DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration Rockville, MD 20857

ANDA 78-293 Mylan Pharmaceuticals Inc. Attention: S. Wayne Talton Vice President, Regulatory Affairs 781 Chestnut Ridge Road P.O. Box 4310 Morgantown, WV 26504-4310 Dear Sir: This is in reference to your abbreviated new drug application (ANDA) dated May 2, 2006, submitted pursuant to section 505(j) of the Federal Food, Drug, and Cosmetic Act (the Act), for Oxybutynin Chloride Extended-release Tablets, 15 mg. Reference is also made to your amendments dated September 29, November 16, and December 14, 2006. We have completed the review of this ANDA, and based upon the information you have presented to date we have concluded that the drug is safe and effective for use as recommended in the submitted labeling. However, we are unable to grant final approval to your ANDA at this time because of the generic drug exclusivity issue issue noted below. Therefore, the ANDA is tentatively approved. This determination is based upon information available to the agency at this time (i.e., information in your ANDA and the status of current good manufacturing practices (cGMPs) of the facilities used in the manufacture and testing of the drug product). This determination is subject to change on the basis of new information that may come to our attention. The listed drug product referenced in your ANDA, Ditropan XL Extended-release Tablets, 15 mg, of Alza Corporation, is subject to periods of patent protection. The following patents and expiration dates are currently listed in the agency’s publication entitled Approved Drug Products with Therapeutic Equivalence Evaluations (the “Orange Book”) for this drug product:

U.S. Patent Number Expiration Date* 5,674,895 (the ‘895 patent) November 22, 2015 5,840,754 (the ‘754 patent) November 22, 2015 5,912,268 (the ‘268 patent) November 22, 2015 6,124,355 (the ‘355 patent) November 22, 2015 6,262,115 (the ‘115 patent) November 22, 2015 6,919,092 (the ‘092 patent) November 22, 2015 *with pediatric exclusivity Your ANDA contains paragraph IV patent certifications under section 505(j)(2)(A)(vii)(IV) of the Act stating that each of these patents is invalid, unenforceable, or will not be infringed by your manufacture, use, sale, offer for sale, or importation of Oxybutynin Chloride Extended-release Tablets, 15 mg, under this ANDA. Section 505(j)(5)(B)(iii) of the Act provides that approval of an ANDA shall be made effective immediately unless an action was brought against Mylan Pharmaceuticals, Inc. (Mylan) for infringement of one or more of these patents that were the subjects of the paragraph IV certifications. This action must have been brought against Mylan prior to the expiration of 45 days from the date the notice you provided under section 505(j)(2)(B) was received by the NDA/patent holder(s). You have notified the agency that Mylan complied with the requirements of section 505(j)(2)(B) of the Act. As a result, litigation for infringement of the ‘355 patent was brought against Mylan in the United States District Court for the Northern District of West Virginia (Alza Corporation v. Mylan Laboratories Inc. and Mylan Pharmaceuticals Inc., Civil Action No. 1:06-cv-125). You informed the agency that Mylan prevailed in the district court with respect to the finding that Mylan did not infringe the asserted claims of the ‘355 patent. Therefore, under section 505(j)(5)(B)(iii)(I), this court decision renders the ANDA eligible for approval. Furthermore, you informed the agency that on October 11, 2005, Alza appealed the district court decision, and that on September 8, 2006, the U.S. Court of Appeals for the Federal Circuit affirmed the district court’s holding that Mylan’s product does not infringe the asserted claims of the patent and that the asserted claims are invalid. The agency recognizes that Mylan was not sued within the 45-day period on any of the other listed patents.

However, we are unable at this time to grant final approval to your ANDA. This is because IMPAX Pharmaceuticals, Inc.’s ANDA 76-745 for Oxybutynin Chloride Extended-release Tablets, 15 mg, approved on November 9, 2006, and containing paragraph IV certifications to the patents listed above, was submitted to the agency prior to the submission of your ANDA. IMPAX’s ANDA is entitled to 180-day generic drug exclusivity for Oxybutynin Chloride Extended-release Tablets, 15 mg. Accordingly, your ANDA will be eligible for final approval on May 9, 2007, the date that is 180 days after the date that IMPAX began commercial marketing as identified in section 505(j)(5)(B)(iv) of the Act. To reactivate your ANDA prior to final approval, please submit a “MINOR AMENDMENT – FINAL APPROVAL REQUESTED” 90 days prior to the expiration of IMPAX’s exclusivity. This amendment should provide the legal/regulatory basis for your request for final approval. It should also identify changes, if any, in the conditions under which the ANDA was tentatively approved; i.e., updated information such as final-printed labeling, chemistry, manufacturing, and controls data as appropriate. This amendment should be submitted even if none of these changes were made, and it should be designated clearly in your cover letter as a MINOR AMENDMENT – FINAL APPROVAL REQUESTED. In addition to the amendment requested above, the agency may request at any time prior to the date of final approval that your submit an additional amendment containing the requested information. Failure to submit either or, if requested, both amendments may result in rescission of the tentative approval status of your ANDA, or may result in a delay of the issuance of the final approval letter. Any significant changes in the conditions outlined in this ANDA as well as changes in the status of the manufacturing and testing facilities’ compliance with current good manufacturing practices (cGMPs) are subject to agency review before final approval of the application will be made. Such changes should be categorized as representing either “major” or “minor” changes, and they will be reviewed according to OGD policy in effect at the time of receipt. The submission of multiple amendments prior to final approval may also result in a delay in the issuance of the final approval letter. This drug product may not be marketed without final agency approval under section 505 of the Act. The introduction or delivery for introduction into interstate commerce of this drug product before the final approval date is prohibited under

section 301 of the Act. Also, until the agency issues the final approval letter, this drug product will not be deemed to be approved for marketing under section 505 of the Act, and will not be listed in the “Orange Book”. For further information on the status of this application, or prior to submitting additional amendments, please contact Leigh Ann Matheny, Project Manager, at (301)-827-5727.

Sincerely yours, {See appended electronic signature page}

Gary Buehler Director Office of Generic Drugs Center for Drug Evaluation and Research

---------------------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.--------------------------------------------------------------------------------------------------------------------- /s/---------------------Robert L. West2/5/2007 09:10:58 AMfor Gary Buehler



LABELING

bladder with symptoms of urge urinary incontinence, urgency, and frequency.Oxybutynin chloride extended-release tablets are also indicated in the

treatment of pediatric patients aged 6 years and older with symptoms of detru-sor overactivity associated with a neurological condition (e.g., spina bifida).

CONTRAINDICATIONS: Oxybutynin chloride extended-release tablets are con-traindicated in patients with urinary retention, gastric retention and other severedecreased gastrointestinal motility conditions, uncontrolled narrow angle glau-coma and in patients who are at risk for these conditions.

Oxybutynin chloride extended-release is also contraindicated in patients whohave demonstrated hypersensitivity to the drug substance or other componentsof the product.

PRECAUTIONS: General: Oxybutynin chloride extended-release should beused with caution in patients with hepatic or renal impairment and in patientswith myasthenia gravis due to the risk of symptom aggravation.Urinary Retention: Oxybutynin chloride extended-release should be adminis-tered with caution to patients with clinically significant bladder outflow obstruc-tion because of the risk of urinary retention (see CONTRAINDICATIONS).Gastrointestinal Disorders: Oxybutynin chloride extended-release shouldbe administered with caution to patients with gastrointestinal obstructive dis-orders because of the risk of gastric retention (see CONTRAINDICATIONS).

Oxybutynin chloride extended-release, like other anticholinergic drugs, maydecrease gastrointestinal motility and should be used with caution in patientswith conditions such as ulcerative colitis and intestinal atony.

Oxybutynin chloride extended-release should be used with caution in pa-tients who have gastroesophageal reflux and/or who are concurrently takingdrugs (such as bisphosphonates) that can cause or exacerbate esophagitis.

As with any other nondeformable material, caution should be used whenadministering oxybutynin chloride extended-release to patients with preexist-ing severe gastrointestinal narrowing (pathologic or iatrogenic). There havebeen rare reports of obstructive symptoms in patients with known strictures inassociation with the ingestion of other drugs in nondeformable controlled-release formulations.Information for Patients: Patients should be informed that heat prostration(fever and heat stroke due to decreased sweating) can occur when anti-cholinergics such as oxybutynin chloride are administered in the presence ofhigh environmental temperature.

Because anticholinergic agents such as oxybutynin may produce drowsiness(somnolence) or blurred vision, patients should be advised to exercise caution.

Patients should be informed that alcohol may enhance the drowsinesscaused by anticholinergic agents such as oxybutynin.

Patients should be informed that oxybutynin chloride extended-releasetablets should be swallowed whole with the aid of liquids. Patients should notchew, divide, or crush tablets.

Oxybutynin chloride extended-release tablets should be taken at ap-proximately the same time each day.Drug Interactions: The concomitant use of oxybutynin with other anticholin-ergic drugs or with other agents which produce dry mouth, constipation, som-nolence (drowsiness), and/or other anticholinergic like effects may increasethe frequency and/or severity of such effects.

Anticholinergic agents may potentially alter the absorption of some con-comitantly administered drugs due to anticholinergic effects on gastrointesti-nal motility. This may be of concern for drugs with a narrow therapeutic index.

Mean oxybutynin chloride plasma concentrations were approximately 2-foldhigher when oxybutynin chloride extended-release tablets were administeredwith ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of thecytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itra-conazole and miconazole) or macrolide antibiotics (e.g., erythromycin andclarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e.,Cmax and AUC). The clinical relevance of such potential interactions is notknown. Caution should be used when such drugs are coadministered.

Concurrent ingestion of antacid (20 mL of antacid containing aluminumhydroxide, magnesium hydroxide, and simethicone) did not significantly affectthe exposure of oxybutynin or desethyloxybutynin.Carcinogenesis, Mutagenesis, Impairment of Fertility: A 24 month study inrats at dosages of oxybutynin chloride of 20, 80 and 160 mg/kg/day showed noevidence of carcinogenicity. These doses are approximately 6, 25 and 50 timesthe maximum human exposure, based on surface area.

Oxybutynin chloride showed no increase of mutagenic activity when testedin Schizosaccharomyces pompholiciformis, Saccharomyces cerevisiae, andSalmonella typhimurium test systems.

Reproduction studies with oxybutynin chloride in the mouse, rat, hamster,and rabbit showed no definite evidence of impaired fertility.Pregnancy: Teratogenic Effects. Pregnancy Category B: Reproductionstudies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showedno definite evidence of impaired fertility or harm to the animal fetus. The safe-ty of oxybutynin chloride extended-release administration to women who are orwho may become pregnant has not been established. Therefore, oxybutyninchloride extended-release should not be given to pregnant women unless, inthe judgment of the physician, the probable clinical benefits outweigh the pos-sible hazards.Nursing Mothers: It is not known whether oxybutynin is excreted in humanmilk. Because many drugs are excreted in human milk, caution should beexercised when oxybutynin chloride extended-release is administered to anursing woman.

Pediatric Use: The safety and efficacy of oxybutynin chloride extended-release were studied in 60 children in a 24 week, open-label trial. Patientswere aged 6 to 15 years, all had symptoms of detrusor overactivity in associ-ation with a neurological condition (e.g., spina bifida), all used clean intermit-tent catheterization, and all were current users of oxybutynin chloride. Studyresults demonstrated that administration of oxybutynin chloride extended-release 5 to 20 mg/day was associated with an increase from baseline inmean urine volume per catheterization from 108 mL to 136 mL, an increasefrom baseline in mean urine volume after morning awakening from 148 mL to189 mL, and an increase from baseline in the mean percentage of catheteri-zations without a leaking episode from 34% to 51%.

Oxybutynin chloride extended-release tablets are not recommended inpediatric patients who cannot swallow the tablet whole without chewing, divid-ing or crushing, or in children under the age of 6 years.Geriatric Use: The rate and severity of anticholinergic effects reported bypatients less than 65 years old and those 65 years and older were similar (seeCLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations:Gender).

ADVERSE REACTIONS: Adverse Events with Oxybutynin ChlorideExtended-release Tablets: The safety and efficacy of oxybutynin chloride wasevaluated in a total of 580 participants who received oxybutynin chlorideextended-release tablets in four clinical trials (429 patients, 151 healthy volun-teers). These participants were treated with 5 to 30 mg/day for up to 4.5months. Three of these studies allowed dose adjustments based on efficacyand adverse events and one was a fixed dose escalation design. Safety infor-mation is provided for 429 patients from these three controlled clinical studiesand one open label study in the first column of Table 3 below. Adverse eventsfrom two additional fixed dose, active controlled, 12 week treatment duration,post-marketing studies, in which 576 patients were treated with oxybutyninchloride extended-release tablets 10 mg/day, are also listed in Table 3 (secondcolumn). The adverse events are reported regardless of causality.

The most common adverse events reported by patients receiving 5 to 30 mg/day oxybutynin chloride extended-release tablets were the expectedside effects of anticholinergic agents. The incidence of dry mouth was doserelated.

The discontinuation rate for all adverse events was 6.8% in the 429 patientsfrom the four studies of efficacy and safety who received 5 to 30 mg/day. Themost frequent adverse event causing early discontinuation of study medica-tion was nausea (1.9%), while discontinuation due to dry mouth was 1.2%.

In addition, the following adverse events were reported by 2 to < 5% of the429 patients who received 5 to 30 mg/day of oxybutynin chloride extended-release tablets in the four efficacy and safety studies. General: abdominal pain,dry nasal and sinus mucous membranes, accidental injury, back pain, flu syn-drome; Cardiovascular: hypertension, palpitation, vasodilatation; Digestive:flatulence, gastroesophageal reflux; Musculoskeletal: arthritis; Nervous: in-somnia, nervousness, confusion; Respiratory: upper respiratory tract infection,cough, sinusitis, bronchitis, pharyngitis; Skin: dry skin, rash; Urogenital: im-paired urination (hesitancy), increased post void residual volume, urinary re-tention, cystitis.

Additional rare adverse events reported from worldwide post-marketingexperience with oxybutynin chloride extended-release tablets include: periph-eral edema, cardiac arrhythmia, tachycardia, hallucinations, convulsions, andimpotence.

Additional adverse events reported with some other oxybutynin chloride for-mulations include: cycloplegia, mydriasis, and suppression of lactation.

OVERDOSAGE: The continuous release of oxybutynin from oxybutynin chlo-ride extended-release tablets should be considered in the treatment of over-dosage. Patients should be monitored for at least 24 hours. Treatment shouldbe symptomatic and supportive. Activated charcoal as well as a cathartic maybe administered.

Overdosage with oxybutynin chloride has been associated with anticholin-ergic effects including central nervous system excitation, flushing, fever, dehy-dration, cardiac arrhythmia, vomiting, and urinary retention.

Ingestion of 100 mg oxybutynin chloride in association with alcohol hasbeen reported in a 13 year old boy who experienced memory loss, and a 34year old woman who developed stupor, followed by disorientation and agita-tion on awakening, dilated pupils, dry skin, cardiac arrhythmia, and retentionof urine. Both patients fully recovered with symptomatic treatment.

DOSAGE AND ADMINISTRATION: Oxybutynin chloride extended-releasetablets must be swallowed whole with the aid of liquids, and must not bechewed, divided, or crushed.

Oxybutynin chloride extended-release tablets may be administered with orwithout food.Adults: The recommended starting dose of oxybutynin chloride extended-release tablets is 5 or 10 mg once daily at approximately the same time eachday. Dosage may be adjusted in 5 mg increments to achieve a balance of effi-cacy and tolerability (up to a maximum of 30 mg/day). In general, dosage adjust-ment may proceed at approximately weekly intervals.Pediatric Patients Aged 6 Years of Age and Older: Pediatric patients aged6 years of age and older: The recommended starting dose of oxybutynin chlo-ride extended-release tablets is 5 mg once daily. Dosage may be adjusted in5 mg increments to achieve a balance of efficacy and tolerability (up to a max-imum of 20 mg/day).

HOW SUPPLIED: Oxybutynin Chloride Extended-release Tablets, USP areavailable containing 15 mg of oxybutynin chloride, USP.

The 15 mg tablets are gray film-coated, round, unscored tablets with M overO 15 imprinted in black ink on one side of the tablet and blank on the otherside. They are available as follows:

NDC 0378-6615-01bottles of 100 tabletsNDC 0378-6615-05

bottles of 500 tablets

Store at 20° to 25°C (68° to 77°F). [See USP for Controlled RoomTemperature.]

Protect from moisture and humidity.Dispense in a tight, light-resistant container as defined in the USP using a

child-resistant closure.

MYLAN®

Mylan Pharmaceuticals Inc.Morgantown, WV 26505

REVISED APRIL 2007OXYBT:R2

Table 3 Incidence (%) of Adverse Events Reported by ≥ 5% of Patients Using Oxybutynin

Chloride Extended-release Tablets (5 to 30 mg/day) and % of CorrespondingAdverse Events in Two Fixed Dose (10 mg/day) Studies

General headacheastheniapain

1077

634

Digestive dry mouthconstipationdiarrheanauseadyspepsia

6113997

297725

Nervous somnolencedizziness

126

24

Respiratory rhinitis 6 2Special blurred visionsenses dry eyes

86

13

Urogenital urinary tractinfection 5 5

Body System Adverse Event

Oxybutynin Chloride ERTablets

5 to 30 mg/day(n = 429)

Oxybutynin Chloride ERTablets

10 mg/day(n = 576)



LABELING REVIEWS

BASIS OF APPROVAL: APPROVAL SUMMARY Container Labels: (bottles of 100 and 500) Professional Package Insert Labeling: Revisions needed post-approval: BASIS OF APPROVAL: Was this approval based upon a petition? No What is the RLD on the 356(h) form: Ditropan XL NDA Number: 18-211 NDA Drug Name: Oxybutinin Extended-release Tablets NDA Firm: Alza Date of Approval of NDA Insert and supplement #: June 30, 2004 Has this been verified by the MIS system for the NDA? Yes Was this approval based upon an OGD labeling guidance? No Basis of Approval for the Container Labels: Basis of Approval for the Carton Labeling: Other Comments NOTES/QUESTIONS TO THE CHEMIST: ________________________________________________________________________________________________________________________________________________________________________ FOR THE RECORD: 1. Review based on the labeling of Ditropan XL by Alza approved June 30, 2004 (NDA 20-897/S013). 2. PATENT/ EXCLUSIVITIES PATENT/ EXCLUSIVITIES

Patent Data – No Expiration Use Code Use File

5674895 May 22, 2015 IV 5674895*PED Nov 22, 2015

5840754 May 22, 2015 IV 5840754*PED Nov 22, 2015

5912268 May 22, 2015 IV 5912268*PED Nov 22, 2015

6124355 May 22, 2015 U-378 Method for treating incontinence IV 6124355*PED Nov 22, 2015 U-378 Method for treating incontinence

6262115 May 22, 2015 U-393 Management of incontinence, mgt of hormone replacement therapy, treatment of involuntary incontinence, mgt

overactive bladder and increasing compliance in such pt

IV

6262115*PED Nov 22, 2015 U-393 Management of incontinence, mgt of hormone replacement therapy, treatment of involuntary incontinence, mgt


6919092 May 22, 2015 U-667 Management of incontinence; method for treating incontinence

IV

6919092*PED Nov 22, 2015

Exclusivity Data - There is no unexpired exclusivity.

3. MANUFACTURING FACILITY Mylan Pharmaceuticals, Inc. 781 Chestnut Ridge Road Morgantown, WV 26505-2730 (Vol. A1.1, p 5424)

_________________________________________________________________________________________ Date of Review: November 28, 2006 Date of Submission: May 2, 2006 Primary Reviewer: Postelle Birch Team Leader: John Grace ________________________________________________________________________________________________________________________________________________________________________ cc: ANDA: 78-293

DUP/DIVISION FILE

---------------------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.--------------------------------------------------------------------------------------------------------------------- /s/---------------------Postelle Birch12/1/2006 02:08:15 PMMEDICAL OFFICER

John Grace12/3/2006 11:30:16 AMMEDICAL OFFICER

APPROVAL SUMMARY REVIEW OF PROFESSIONAL LABELING

DIVISION OF LABELING AND PROGRAM SUPPORT LABELING REVIEW BRANCH

____________________________________________________________________________________ ____________________________________________________________________________________ ANDA Number: 78-293 Date of Submission: December 14, 2006 Applicant's Name: Mylan Pharmaceuticals, Inc. Established Name: Oxybutinin Chloride Extended-release Tablets, 15 mg ____________________________________________________________________________________ ____________________________________________________________________________________ BASIS OF APPROVAL: APPROVAL SUMMARY CONTAINER LABELS: (bottles of 100 and 500) Satisfactory in FPL as of December 14, 2006 e-submission. PROFESSIONAL PACKAGE INSERT: Satisfactory in FPL as of December 14, 2006 e-submission. BASIS OF APPROVAL: Was this approval based upon a petition? No What is the RLD on the 356(h) form: Ditropan XL NDA Number: 18-211 NDA Drug Name: Oxybutinin Extended-release Tablets NDA Firm: Alza Date of Approval of NDA Insert and supplement #: June 30, 2004 Has this been verified by the MIS system for the NDA? Yes Was this approval based upon an OGD labeling guidance? No Basis of Approval for the Container Labels: side-by-side Basis of Approval for the Carton Labeling: side-by-side Other Comments FOR THE RECORD: 1. Review based on the labeling of Ditropan XL by Alza approved June 30, 2004 (NDA 20-897/S013). 2. PATENT/ EXCLUSIVITIES PATENT/ EXCLUSIVITIES


5674895 May 22, 2015 IV 5674895*PED Nov 22, 2015

5840754 May 22, 2015 IV 5840754*PED Nov 22, 2015

5912268 May 22, 2015 IV 5912268*PED Nov 22, 2015




IV



6919092 May 22, 2015 U-667 Management of incontinence; method for treating IV

The desiccant is manufactured by and consists of a canister containing black activated carbon and silica gel granules. This is the same as in the 75mL bottle.

(p. 5706 ) 9. The 15 mg tablets are gray, film-coated, round, unscored tablets with M over O 15 imprinted in black ink on

one side of the tablet and blank on the other side. 10. Mylan also has 5 mg (76-702) and 10 mg (76-644) extended release tablets. ______________________________________________________________________________________________________________________________________________________________________________________ Date of Review: January 8, 2007 Date of Submission: December 14, 2006 Primary Reviewer: Postelle Birch-Smith Team Leader: John Grace ________________________________________________________________________________________________________________________________________________________________________ cc: ANDA: 78-293

DUP/DIVISION FILE

(b) (4)

(b) (4) (b) (4)

This approval summary supersedes the December 14, 2006 approval summary. APPROVAL SUMMARY REVIEW OF PROFESSIONAL LABELING

DIVISION OF LABELING AND PROGRAM SUPPORT LABELING REVIEW BRANCH

____________________________________________________________________________________ ____________________________________________________________________________________ ANDA Number: 78-293 Dates of Submission: May 2, 2007 and April 17, 2007 Applicant's Name: Mylan Pharmaceuticals, Inc. Established Name: Oxybutynin Chloride Extended-release Tablets USP, 15 mg ____________________________________________________________________________________ ____________________________________________________________________________________ BASIS OF APPROVAL: APPROVAL SUMMARY CONTAINER LABELS: (bottles of 100 and 500) Satisfactory in FPL as of April 17, 2007 e-submission. PROFESSIONAL PACKAGE INSERT: Satisfactory in FPL as of May 2, 2007 e-submission. BASIS OF APPROVAL: Was this approval based upon a petition? No What is the RLD on the 356(h) form: Ditropan XL NDA Number: 18-211 NDA Drug Name: Oxybutinin Extended-release Tablets NDA Firm: Alza Date of Approval of NDA Insert and supplement #: June 30, 2004 Has this been verified by the MIS system for the NDA? Yes Was this approval based upon an OGD labeling guidance? No Basis of Approval for the Container Labels: side-by-side Basis of Approval for the Carton Labeling: side-by-side Other Comments FOR THE RECORD: 1. Review based on the labeling of Ditropan XL by Alza approved June 30, 2004 (NDA 20-897/S013). 2. PATENT/ EXCLUSIVITIES


5674895 May 22, 2015 IV 5674895*PED Nov 22, 2015

5840754 May 22, 2015 IV 5840754*PED Nov 22, 2015

5912268 May 22, 2015 IV 5912268*PED Nov 22, 2015




IV


.

The desiccant is manufactured by and consists of a canister containing black activated carbon and silica gel granules. This is the same as in the 75mL bottle.

(p. 5706 ) 9. The 15 mg tablets are gray, film-coated, round, unscored tablets with M over O 15 imprinted in black ink on

one side of the tablet and blank on the other side. 10. Mylan also has 5 mg (76-702) and 10 mg (76-644) extended release tablets. ______________________________________________________________________________________________________________________________________________________________________________________ Date of Review: May 1, 2007 Dates of Submission: May 2, 2007 and April 17, 2007 Primary Reviewer: Postelle Birch-Smith Team Leader: John Grace ________________________________________________________________________________________________________________________________________________________________________ cc: ANDA: 78-293

DUP/DIVISION FILE

(b) (4)

(b) (4) (b) (4)



CHEMISTRY REVIEWS

---------------------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.--------------------------------------------------------------------------------------------------------------------- /s/---------------------Robert Iser1/31/2007 04:20:02 PMCHEMIST

Devinder Gill1/31/2007 05:46:38 PMCHEMIST

Leigh Matheny1/31/2007 06:31:02 PMCSO

---------------------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.--------------------------------------------------------------------------------------------------------------------- /s/---------------------Robert Iser5/9/2007 11:53:10 AMCHEMISTapprovable

Devinder Gill5/9/2007 01:02:13 PMCHEMIST

Leigh Matheny5/11/2007 09:03:47 AMCSO



BIOEQUIVALENCE REVIEWS

1

DIVISION OF BIOEQUIVALENCE REVIEW

ANDA No. 78-293 Drug Product Name Oxybutynin Chloride Extended-Release Tablets Strength 15 mg Applicant Name Mylan Pharmaceuticals Inc. Address 781 Chestnut Ridge Road, Morgantown, WV 26504 Contact Person S. Wayne Talton

Phone (304) 599-2595 Fax (304) 285-6407

Submission Date(s) May 2, 2006 Amendment Date(s) October 12, 2006 (Dissolution) Reviewer Sarah M. Robertson, Pharm.D. First Generic No I. Executive Summary

The firm previously received approval for Oxybutynin Cl Extended-Release Tablets, 5 mg (ANDA 76-702) and 10 mg (ANDA 76-644) on Nov. 9, 2006, based on acceptable results of fasted and fed bioequivalence studies. This submission consists of one fasting bioequivalence (BE) study and dissolution data for the 15 mg strength tablet. The firm requests a biowaiver for the fed BE study requirement.

The two-way crossover fasting BE study comparing Oxybutynin Cl Extended-Release Tablets, 15 mg to the reference listed drug (RLD), Ditropan® XL (Alza Corp.) was conducted in healthy adult males and females (n = 77). The firm measured plasma levels of both oxybutynin and the active metabolite, desethyloxybutynin. However, only oxybutynin is considered in order to establish bioequivalence. The results (point estimate, 90% CI) for oxybutynin are LAUCt of 0.99, 90.7 – 107.0%; LnAUCi of 0.98, 89.9 – 106.2%; and LnCmax of 0.92, 85.0 – 100.0%. The fasting study is acceptable. A waiver of BE is granted for the fed study requirement.

The dissolution data submitted by the firm is acceptable. The application is complete.

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II. Table of Contents I. Executive Summary ........................................................................................................................................1 II. Table of Contents ........................................................................................................................................2 III. Submission Summary..................................................................................................................................2

A. Drug Product Information .......................................................................................................................2 B. PK/PD Information .................................................................................................................................3 C. Contents of Submission...........................................................................................................................4 D. Pre-Study Bioanalytical Method Validation ...........................................................................................5 E. In Vivo Studies........................................................................................................................................5

1. Single-dose Fasting Bioequivalence Study .............................................................................................5 F. Formulation.............................................................................................................................................7 G. In Vitro Dissolution ................................................................................................................................7 H. Waiver Request(s)...................................................................................................................................8 I. Deficiency Comments.............................................................................................................................8 J. Recommendations...................................................................................................................................9

IV. Appendix...................................................................................................................................................10 A. Individual Study Reviews .....................................................................................................................10

1. Single-dose Fasting Bioequivalence Study ...........................................................................................10 a) Study Design.....................................................................................................................................10 b) Clinical Results .................................................................................................................................12 c) Bioanalytical Results ........................................................................................................................14 d) Pharmacokinetic Results ...................................................................................................................15

B. Formulation Data ..................................................................................................................................20 C. Dissolution Data....................................................................................................................................25 D. SAS Output ...........................................................................................................................................22

III. Submission Summary

A. Drug Product Information

Test Product Oxybutynin Cl Extended-Release Tablets, 15 mg Reference Product Ditropan® XL 15 mg Tablets RLD Manufacturer Alza Corporation NDA No. 20-897 RLD Approval Date Dec 16, 1998 Indication Treatment of Overactive Bladder

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B. PK/PD Information

Bioavailability 6% Food Effect None Tmax 4 – 6 hours Metabolism Extensively metabolized via enteric and hepatic CYP450

3A4 enzymes. Desethyloxybutynin is an active metabolite.

Excretion < 0.1% of oxybutynin or N-desethyloxybutynin appears in the urine unchanged

Half-life 12 hours (post-prandial) and 16 hours (fasting) (extended-release formulation)

Relevant OGD or DBE History There is one approved generic for the 15 mg strength tablet (76-745, Impax). Mylan Pharmaceuticals Inc. received approval of their 10 mg and 5 mg strength tablets Nov. 9, 2006 (76-644, 76-702) following resolution of a pending Citizen Petition filed by Ortho Urology. This is currently the only pending ANDA submission. The Division has responded to 13 control documents (99-276, ; 00-025, 00-496

; 00-517, 01-297, ; 02-059, 02-034, 02-390, 04-203, 04-603, 05-1194, Ortho Urology - Citizen Petition; 06-0282, 06-0822,

. The Division of Bioequivalence (DBE) recommends measurement of both oxybutynin and its active metabolite, desethyloxybutynin, using an achiral assay, without measurement of the individual enantiomers, in bioequivalence studies of Oxybutynin HCl Extended Release Tablets.

DBE recommends measurement of desethyloxybutynin because it is formed as a result of presystemic metabolism and contributes meaningfully to efficacy. However, only the parent compound, oxybutynin, should be analyzed using the confidence interval approach to establish bioequivalence. This recommendation is consistent with the CDER Guidance, Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations, March, 2003.

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The DBE recommends the same dissolution method as used for the firm’s 5 mg and 10 mg strength tablets: Medium: Row 1 – pH 1.2 Simulated Gastric Fluid w/out enzymes. Row 2 - 4 – pH 6.8 Simulated Intestinal Fluid w/out enzymes. Apparatus: Apparatus 3 (reciprocating cylinder) Volume: 250 mL Temp.: 37ºC ± 0.5ºC

Speed: 25 dips per min. Spec.:

Agency Guidance Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations, March, 2003.

Drug Specific Issues (if any) None

B. Contents of Submission

Study Types Yes/No? How many? Single-dose fasting Yes 1 Single-dose fed No Steady-state No In vitro dissolution Yes 1 Waiver requests Yes 1 (for fed study) BCS Waivers No Vasoconstrictor Studies No Clinical Endpoints No Failed Studies No Amendments Yes 1 (dissolution)

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C. Pre-Study Bioanalytical Method Validation

Parent Metabolite Analyte name Oxybutynin N-Desethyloxybutynin Internal Standard Method description LC/MS LC/MS

QC range 150.84 – 7039.20 pg/mL 299.28 – 13966.00 pg/mL Standard curve range 50.16 – 10032.00 pg/mL 100.24 – 20048.00 pg/mL Limit of quantitation 50.16 pg/mL 100.24 pg/mL Inter-assay precision of analytical standards (CV%)

2.11 – 4.40 2.30 – 6.12

Inter-assay accuracy of analytical standards (%)

97.76 – 102.63 95.43 – 102.14

Linearity r2 > 0.9984 r2 > 0.9983 Average recovery of Drug (%) 65.06, 61.31, 66.05% 72.81, 68.35, 72.89% Average Recovery of Int. Std (%) 75.86 75.86 QC Intraday precision range (%) 1.61 – 3.35 2.92 – 7.18 QC Intraday accuracy range (%) 96.86 – 101.05 96.95 – 103.12 QC Interday precision range (%) 3.26 – 4.07 3.26 – 4.07 QC Interday accuracy range (%) 100.60 – 104.44 98.32 – 100.80 Bench-top stability (hrs) 110 min. at RT 110 min. at RT Processed stability (hrs) 76 hrs. at RT 76 hrs. at RT Freeze-thaw stability (cycles) 4 4 Stock Solution Stability 202 days at -200C, and 6 hours at RT 202 days at -200C, and 6 hours at RT Long-term storage stability 166 days at-800C 166 days at-800C Dilution integrity 2 x (CV% 1.39)

20 x (CV% 2.39) 2 x (CV% 3.04 20 x (CV% 2.88)

Specificity No interfering peaks noted in blank plasma samples

No interfering peaks noted in blank plasma samples

E. In Vivo Studies

1. Single-dose Fasting Bioequivalence Study

Study Summary Study No. OXYB-05129 Study Design Single-dose, two-way crossover study conducted

in healthy volunteers under fasting conditions. No. of subjects enrolled 80 No. of subjects completing 77 (Subj#15 withdrew prior to Period 2 for

personal reasons, Subj#37 and #52 were withdrawn prior to Period 2 due to adverse events)

No. of subjects analyzed 77 Subjects (Healthy or Patients?) Healthy Sex(es) included (how many?) Males 42; Females 35 Test product Oxybutynin Chloride Extended-Release Tablets Reference product Ditropan® XL Tablets Strength tested 15 mg Dose 1 x 15 mg

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Summary of Statistical Analysis Metaxalone (N=77) Parameter Point Estimate 90% Confidence Interval AUC0-t 0.99 90.68 – 107.02 AUC∞ 0.98 89.86 – 106.16 Cmax 0.92 85.01 – 100.03 Table 1. Reanalysis of Study Samples

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H. Waiver Request(s)

The firm requests a biowaiver for the fed study requirement based on the following: (1) Acceptable results for the fed BE study conducted with 10 mg strength tablets included in ANDA 76-644, (2) Proportionality of formulation for the 10 mg and 15 mg strength tablets, and (3) Acceptable comparative dissolution

The dissolution is acceptable, and the 10 mg and 15 mg formulations are proportional. The waiver is granted.

I. Deficiency Comments

None

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J. Recommendations

1. The BE study conducted by Mylan Pharmaceuticals Inc. on the test product Oxybutynin Cl Extended-Release Tablets, 15 mg, Lot #R1N3882, comparing it to the RLD Ditropan® XL Tablets, 15 mg, Lot #0531572, under fasting conditions, is acceptable. A waiver is granted for the fed BE study requirement.

2. The dissolution testing conducted by the firm on its drug product Oxybutynin Cl

Extended-Release Tablets, 15 mg, is acceptable. The dissolution testing should be conducted in 250 mL of pH 1.2 Simulated Gastric Fluid without enzymes (Row 1) and 250 mL of pH 6.8 Simulated Intestinal Fluid without enzymes (Rows 2-4), at 37ºC, using Apparatus III (reciprocating cylinder) at 25 dpm.

The test products should meet the following specifications:

2 hours: Between 0% and 10% 4 hours: Between 10% and 30% 8 hours: Between 35% and 60% 16 hours: NLT 75% Sarah M. Robertson, Pharm.D. Date Review Branch III Chandra S. Chaurasia, Ph.D. Date Acting Team Leader, Review Branch III Dale P. Conner, Pharm. D. Date Director, Division of Bioequivalence Office of Generic Drugs

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IV. Appendix A. Individual Study Reviews

1. Single-dose Fasting Bioequivalence Study

a) Study Design

Study Information Study Number OXYB-05129 Study Title Single-Dose Fasting Bioequivalence Study of

Oxybutynin Chloride Extended-Release Tablets (15 mg; Mylan) to Ditropan® XL Tablets (15 mg; ALZA) in Healthy Volunteers.

Clinical Site PRACS Institute, Ltd.,East Grand Forks, MN Principal Investigator James D. Carlson, Pharm.D. Study/Dosing Dates Period I: January 20 – 24, 2006

Period II: January 27 – 31, 2006 Analytical Site Analytical Director Ph.D. Analysis Dates February 10 – March 20, 2006 Storage Period (no. of days from the first day of sample collection to the last day of sample analysis)

59 Days

Treatment ID Test Reference Test or Reference A B Product Name Oxybutynin Chloride

Extended-Release Tablet Ditropan® XL Tablet

Manufacturer Mylan Pharmaceuticals Inc.

ALZA Corporation

Batch/Lot No. R1N3882 0531572 Manufacture Date 12/14/2005 N/A Expiration Date N/A 03/2007 Strength 15 mg 15 mg Dosage Form Tablet Tablet Batch Size N/A Production Batch Size N/A Potency 97.9% 99.4% Content Uniformity (mean, %RSD) 98.4% (1.5% RSD) 99.9% (2.3% RSD) Formulation See Appendix B Dose Administered 1 x 15 mg 1 x 15 mg Route of Administration Oral

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No. of Sequences 2 No. of Periods 2 No. of Treatments 2 No. of Groups 1 Washout Period 7 Days Randomization Scheme AB: 3, 4, 5, 6, 10, 11, 14, 16 – 18, 23, 24, 26, 28, 30,

32, 33, 36 – 38, 41, 42, 46, 47, 49, 50, 53, 55, 58, 59, 61, 63, 66, 67, 70, 71, 74, 75, 78, 80 BA: 1, 2, 7 – 9, 12, 13, 15, 19 – 22, 25, 27, 29, 31, 34, 35, 39, 40, 43 – 45, 48, 51, 52, 54, 56, 57, 60, 62, 64, 65, 68, 69, 72, 73, 76, 77, 79

Blood Sampling Times 0 and at 1, 2, 4, 5, 6, 8, 10, 12, 14, 16, 18, 21, 24, 28, 36, 48, 60, and 72 hrs post dose.

Blood Volume Collected/Sample 1 x 10 mL Blood Sample Processing/Storage Plasma samples separated and stored at - 700C + 150C IRB Approval Yes Informed Consent Yes Subjects Demographics See Table 1 Length of Fasting 10 hrs prior to drug administration and until 4 hrs after Length of Confinement 10 hrs prior to drug administration and until 24-hr

blood draw Safety Monitoring Yes, vital signs were measured prior to and at 12 and

24 h after dosing Comments on Study Design: Acceptable

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b) Clinical Results

Table 1. Demographics of Study Subjects

Table 2. Dropout Information

Subject No Reason Period Replaced? 15 Withdrew consent due to

personal reasons Prior to Period 2 No

37 Withdrawn from study by investigator due to adverse event (vomiting)

Prior to Period 2 No

52 Withdrawn from study by investigator due to adverse event (vomiting)

During Period 1 No

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Table 3. Study Adverse Events

Table 4. Protocol Deviations

Two subjects reported medication use during the study:

Subject No. Drug Dose Start Date Stop Date68 Acetaminophen 2 x 325 mg 1/30/06 1/30/06 75 Acetaminophen 2 x 325 mg 1/22/06 1/22/06

Deviations to the blood-draw schedule are shown in Section 16.2.6. (Volume 1.7, page 3195). Comments on Dropouts/Adverse Events/Protocol Deviations:

As judged by the investigator the adverse events and protocol deviations did not compromise the integrity of the study.

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Figure 1. Mean Plasma Concentration-Time Plot (Parent)

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Figure 2. Mean Plasma Concentration-Time Plot (Metabolite)

Summary and Conclusions, Single-Dose Fasting Bioequivalence Study: The study is acceptable.

01:53 Wednesday, November 29, 2006 22D. SAS Output (b) (4)

Following this page, 29 pages withheld in full (b)(4) SAS Output

BIOEQUIVALENCE COMMENTS TO BE PROVIDED TO THE APPLICANT ANDA: 78-293 APPLICANT: Mylan Pharmaceuticals Inc. DRUG PRODUCT: Oxybutynin Chloride Extended Release Tablets, 15 mg The Division of Bioequivalence (DBE) has completed its review of your submission and has no further questions at this time. We agree with your proposed dissolution method and specifications as follows: The dissolution testing should be conducted in 250 mL of pH 1.2 Simulated Gastric Fluid without enzymes (Row 1) and 250 mL of pH 6.8 Simulated Intestinal Fluid without enzymes (Rows 2-4), at 37ºC, using Apparatus III (reciprocating cylinder) at 25 dpm. The test product should meet the following specifications:

2 hours: Between 0% and 10% 4 hours: Between 10% and 30% 8 hours: Between 35% and 60% 16 hours: NLT 75%

Please note that the bioequivalence comments provided in this communication are preliminary. These comments are subject to revision after review of the entire application, upon consideration of the chemistry, manufacturing and controls, microbiology, labeling, or other scientific or regulatory issues. Please be advised that these reviews may result in the need for additional bioequivalence information and/or studies, or may result in a conclusion that the proposed formulation is not approvable. Sincerely Yours, Dale P. Connor, Pharm.D. Director, Division of Bioequivalence Office of Generic Drugs Center for Drug Evaluation and Research

CC: ANDA 78-293 BIOEQUIVALENCE – Acceptable Submission dates: May 2, 2006 1. FASTING STUDY (STF) Strength: 15 mg Clinical: PRACS Institute, Ltd.,East Grand Forks, MN Analytical: Outcome: AC OUTCOME DECISIONS: The fasting BE study is acceptable. A waiver of is granted for the fed BE study requirement.

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---------------------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.--------------------------------------------------------------------------------------------------------------------- /s/---------------------Sarah M. Robertson11/29/2006 02:02:48 PMBIOPHARMACEUTICS

Chandra S. Chaurasia11/29/2006 02:18:29 PMBIOPHARMACEUTICS

Barbara Davit11/30/2006 01:14:57 PMBIOPHARMACEUTICS

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DBE METHOD RECOMMENDED FOR THE 5 MG (ANDA 76-702) AND 10 MG (ANDA 76-644) STRENGTHS Medium* Row 1: pH 1.2 Simulated Gastric Fluid without enzymes

Rows 2-4: pH 6.8 Simulated Intestinal Fluid without enzymesVolume 250 mL Temperature 37 ºC ± 0.5°C Apparatus Apparatus 3 (reciprocating cylinder) Rotational Speed 25 dpm (dips per minute) Specifications (5 and 10 mg strengths only) 2 hr:

4 hr: 8 hr: 16 hr:

*The tablet is automatically transferred by the apparatus to the next set of vessels for each time point that is programmed. Therefore, Row 1 corresponds to the 2-hour time point, Row 2 corresponds to the 4-hour time point, Row 3 corresponds to the 8-hour time point, and Row 4 corresponds to the 16-hour time point.

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BIOEQUIVALENCE COMMENTS TO BE PROVIDED TO THE APPLICANT

ANDA: 78-293 APPLICANT: Mylan Pharmaceuticals, Inc. DRUG PRODUCT: Oxybutynin Chloride Extended-Release Tablets, 15 mg The Division of Bioequivalence has completed its review of dissolution testing data submitted in the application and has no further questions at this time. The review of the bioequivalence study and waiver request will be conducted later. We agree with your proposed dissolution method and specifications as follows: The dissolution testing should be conducted in 250 mL of pH 1.2 Simulated Gastric Fluid without enzymes (Row 1) and 250 mL of pH 6.8 Simulated Intestinal Fluid without enzymes (Rows 2-4), at 37ºC, using Apparatus III (reciprocating cylinder) at 25 dpm. The test products should meet the following specifications:

2 hours: Between 0% and 10% 4 hours: Between 10% and 30% 8 hours: Between 35% and 60% 16 hours: NLT 75%

Sincerely yours,

Dale P. Conner, Pharm.D. Director, Division of Bioequivalence Office of Generic Drugs Center for Drug Evaluation and Research

BIOEQUIVALENCE –ACCEPTABLE Submission Date: 10/12/2006 [NOTE: The in vitro testing is complete. The fasted BE study and waiver request are pending review.] 1. BDI Strength: 15 mg Outcome Decisions: AC – Acceptable WinBio Comments: AC

---------------------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.--------------------------------------------------------------------------------------------------------------------- /s/---------------------Sheryl Gunther12/14/2006 01:30:24 PMBIOPHARMACEUTICS

Diem-Kieu Ngo12/14/2006 01:33:00 PMBIOPHARMACEUTICS

Barbara Davit12/18/2006 10:17:53 AMBIOPHARMACEUTICS



ADMINISTRATIVE and CORRESPONDENCE DOCUMENTS

M E M O R A N D U M DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH _____________________________________________________________________________ DATE: November 9, 2006 FROM: Cecelia M. Parise Regulatory Policy Advisor to the Director Office of Generic Drugs Center for Drug Evaluation and Research THROUGH: Robert L. West Deputy Director Office of Generic Drugs Center for Drug Evaluation and Research TO: ANDAs for Oxybutynin Extended-release Tablets 76-644, Mylan Pharmaceuticals 76-702, Mylan Pharmaceuticals 78-293, Mylan Pharmaceuticals 76-745, Impax Pharmaceuticals SUBJECT: Enantiomers Please see the attached memo from the Division of Reproductive and Urologic Drug Products (DRUP). The memo states that there is insufficient evidence to support the notion that R-oxybutynin is the enantiomer primarily responsible for efficacy, and that the absorption of the enantiomers is linear. Therefore, the decision by the Division of Bioequivalence not to apply confidence interval criteria to the enantiomers in order to establish bioequivalence for Oxybutynin Extended-release Tablets for the same reasons outlined in the memo from DRUP still stands and remains correct.

---------------------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.--------------------------------------------------------------------------------------------------------------------- /s/---------------------Patricia L. Downs11/9/2006 10:09:10 AMSECRETARY

Cecelia Parise11/9/2006 10:16:36 AMCSO

Robert L. West11/9/2006 10:36:16 AMCSO

Telephone Fax ANDA 78-293 OFFICE OF GENERIC DRUGS, CDER, FDA Document Control Room, Metro Park North I 7520 Standish Place Rockville, MD 20855-2773 301-827-7347

TO: Mylan Pharmaceuticals, Inc. ATTN: S. Wayne Talton FROM: Postelle Birch-Smith, Pharm. D.

TEL: 304-599-2595 FAX: 304-285-6407

Dear Sir: This facsimile is in reference to your abbreviated new drug application submitted pursuant to Section 505(j) of the Federal Food, Drug, and Cosmetic Act for Oxybutinin Chloride Extended-release Tablets, 15 mg. Pages (including cover): 3 SPECIAL INSTRUCTIONS: Labeling Comments THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL, OR PROTECTED FROM DISCLOSURE UNDER APPLICABLE LAW. If received by someone other than the addressee or a person authorized to deliver this document to the addressee, you are hereby notified that any disclosure, dissemination, copying, or other action to the content of this communication is not authorized. If you have received this document in error, please immediately notify us by telephone and return it to us by mail at the above address.

---------------------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.--------------------------------------------------------------------------------------------------------------------- /s/---------------------John Grace12/3/2006 11:31:04 AMfor Wm Peter Rickman

OGD APPROVAL ROUTING SUMMARY ANDA # 78-293 ApplicantMylan Pharmaceuticals, Inc. Drug Oxybutynin Chloride Extended Release Tablets USP Strength(s)15 mg APPROVAL TENTATIVE APPROVAL SUPPLEMENTAL APPROVAL (NEW STRENGTH) OTHER REVIEWER: DRAFT Package FINAL Package 1. Martin Shimer Chief, Reg. Support Branch

Contains GDEA certification: Yes No Determ. of Involvement? Yes No (required if sub after 6/1/92) Pediatric Exclusivity System RLD = NDA# Patent/Exclusivity Certification: Yes No Date Checked If Para. IV Certification- did applicant Nothing Submitted Notify patent holder/NDA holder Yes No Written request issued Was applicant sued w/in 45 days:Yes No Study Submitted Has case been settled: Yes No Date settled: Is applicant eligible for 180 day Generic Drugs Exclusivity for each strength: Yes No Date of latest Labeling Review/Approval Summary Any filing status changes requiring addition Labeling Review Yes No Type of Letter:Full Approval Comments:Mylan filed PIV certifications to all listed patents. Alza initiated suit

against Mylan[1:06CV-125-IMK] in the Northern District of WV on 8/21/2006. This suit was withdrawn by Alza on September 8, 2006. Ergo, there is no remaining 30 month stay prohibiting approval of this ANDA. IMPAX ANDA 76-745 holds 180 day exclusivity for this drug product until 5/9/2007. This ANDA will be eligible for Full Approval on 5/9/2007. 2. Project Manager, Leigh Ann Matheny Team 4 Review Support Branch

Original Rec′d date 5/2/06 EER Status Pending Acceptable OAI Date Acceptable for Filing5/3/06 Date of EER Status 7/10/06 Patent Certification (type)IV Date of Office Bio Review 11/30/06 Date Patent/Exclus.expires5/22/2012 Date of Labeling Approv. Sum Citizens' Petition/Legal Case Yes No (If YES, attach email from PM to CP coord)

Date of Sterility Assur. App. n/a Methods Val. Samples Pending Yes No

First Generic Yes No MV Commitment Rcd. from Firm Yes No Priority Approval Yes No (If yes, prepare Draft Press Release, Email it to Cecelia Parise)

Modified-release dosage form: Yes No Interim Dissol. Specs in AP Ltr: Yes

Acceptable Bio reviews tabbed Yes No Bio Review Filed in DFS: Yes No Suitability Petition/Pediatric Waiver Pediatric Waiver Request Accepted Rejected Pending Previously reviewed and tentatively approved Date 2/5/07 Previously reviewed and CGMP def. /NA Minor issued Date

Comments: 3. Labeling Endorsement Reviewer: Labeling Team Leader:

Comments: 4. David Read (PP IVs Only) Pre-MMA Language included Date 5/7/07 OGD Regulatory Counsel, Post-MMA Language Included InitialsDTR

Comments:Changes to Ap Ltr saved to V drive.

Date1 May 2007 Date InitialsMHS Initials

Date4/26/07 Date InitialsLM Initials

Date5/8/07 Date5/8/07 Name/InitialsP.B. Name/InitialsJ.G.

5. Div. Dir./Deputy Dir. Chemistry Div. III

Comments:cmc acceptable 6. Frank Holcombe First Generics Only Date Assoc. Dir. For Chemistry Initials Comments: (First generic drug review) 7. Vacant Date Deputy Dir., DLPS Initials 8. Peter Rickman Date5/10/2007 Director, DLPS Initialswpr

Para.IV Patent Cert: Yes No ;Pending Legal Action: Yes No ; Petition: Yes No Comments:Mylan filed PIV patents certs to all listed patents. Alza initiated litigation, but withdrew 9/8/2006. No remaining 30 month stay. Eligible for full approval after Impax 180 day exclusivity expires 5/9/2007; W/H exclusivity expired 10/15/2006; labeling acceptable 5/8/2007; bio acceptable 11/30/2006 (single dose fasting); EER acceptable 7/10/2006. okay for full approval OR 8. Robert L. West Date Deputy Director, OGD Initials Para.IV Patent Cert: Yes No ; Pending Legal Action: Yes No ; Petition: Yes No Press Release Acceptable Comments: 9. Gary Buehler Date

Director, OGD Initials Comments: First Generic Approval PD or Clinical for BE Special Scientific or Reg.Issue

Press Release Acceptable 10. Project Manager, Leigh Ann Matheny Team 4 Date5/10/07

Review Support Branch Initials LK for Date PETS checked for first generic drug (just prior to notification to firm) Applicant notification: 2:55 PM Time notified of approval by phone 2:58 PM Time approval letter faxed FDA Notification: 5/10/07 Date e-mail message sent to "CDER-OGDAPPROVALS″ distribution list. 5/10/07 Date Approval letter copied to \\CDS014\DRUGAPP\ directory.

Date5/9/07 InitialsVAS

---------------------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.--------------------------------------------------------------------------------------------------------------------- /s/---------------------Lisa Kwok5/10/2007 03:03:53 PM